Methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction

ABSTRACT

Methods for the prevention, treatment, or management of sexual dysfunction, such as premature ejaculation, by administering to a patient in need of therapy a therapeutically effective amount of a rapid-onset selective serotonin reuptake inhibitor on an as-needed basis shortly before sexual activity.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.10/049,427, filed May 6, 2002, which is a national stage applicationunder 35 U.S.C § 371 of International Application No. PCT/US00/20788,filed Aug. 22, 2000, which claims the benefit of priority to U.S.Provisional Patent Application No. 60/152,435, filed Sep. 3, 1999, eachof which is incorporated herein, in its entirety, by this reference.

FIELD OF THE INVENTION

The invention relates to methods for the prevention, treatment, ormanagement of sexual dysfunction in mammals, particularly prematureejaculation in men, by administering a therapeutically effective amountof a rapid onset selective serotonin reuptake inhibitor, or apharmaceutically acceptable salt o thereof, on an as-needed basisshortly before sexual activity.

BACKGROUND OF THE INVENTION

A normal erection occurs as a result of a coordinated vascular event inthe penis, which is usually triggered neurally and includes vasodilationand smooth muscle relaxation in the penis and its supplying arterialvessels. Arterial inflow causes enlargement of the substance of thecorpora cavernosa. Venous outflow is trapped by this enlargement,permitting sustained high blood pressures in the penis normallysufficient to cause rigidity. Muscles in the perineum also assist increating and maintaining penile rigidity. Erection may also be inducedcentrally in the nervous system by sexual thoughts or fantasy, and isusually reinforced locally by reflex mechanisms. Erectile mechanics inwomen are substantially similar for the clitoris. In men, however,ejaculation typically occurs with an orgasm.

Premature ejaculation, however, is one of the most common sexualcomplaints. It is estimated to affect up to 30 to 40 percent of men,i.e., approximately 36 million American men (Derogatis, L. R., Med.Aspects Hum. Sexuality, 14:1168-76 (1980); Frank E., et al., Engl. J.Med., 299:111-115 (1978); Schein, M., et al., Fam. Pract. Res. J., 7(3):122-134 (1988)). Premature ejaculation means persistent or recurrentejaculation with minimal sexual stimulation before, upon, or shortlyafter penetration, and before the person wishes it. Such ejaculationthat occurs sooner than desired is often disappointing and can lead toother sexual dysfunctions including erectile difficulties, femaleinorgasmia, low sexual desire, and sexual aversion (Rust J., et al., Br.J. Psychiat, 152:629-631 (1988)). Behavioral therapy, such as the Semanspause maneuver, the Masters and Johnson pause-squeeze technique or theKaplan stop-start method, is considered the gold standard for thetreatment of premature ejaculation (Seftel, A. D., Altohob, S. E.,“Premature Ejaculation”, Diagnosis and Management of Male SexualDysfunction, Edited by J. J. Mulcahy, New York, N.Y., Igaku-Shoin,(1997) Chapter 11, pages 196-203). While these techniques are harmless,usually painless, and are successful at rates of 60 to 95% (ibid;Hawton, K., et al., Behav. Res. Ther., 24:377 (1986)), they requirepartner cooperation and improvement is short-lived (Bancroft, J. andColes, L., Brit. Med. J. 1:1575 (1976) and De Amicus, L. A., et al.,Arch. Sex. Behav., 14:467 (1985)).

Premature ejaculation rarely has a physical cause, however, prostategland inflammation or nervous system disorders may be involved.Treatment may involve certain selective serotonin reuptake inhibitors,such as fluoxetine, paroxetine, or sertraline (Merck Manual of MedicalInformation at 421-422, Home Edition, Merck Research Laboratories(1997)); see also U.S. Pat. No. 5,597,826 (sertraline), U.S. Pat. No.5,276,042 (paroxetine), and U.S. Pat. No. 5,151,448 (fluoxetine).

Although ejaculation latency is affected by psychological and/orcognitive mechanisms, somatic factors are also involved (Althof, S. E.,Psychiatr. Clin. N. Amer., 18(1):85-94 (1995); Rowland, D. L., et al.,J. Sex. Marital. Ther., 19:189 (1993)). Ejaculation is mediated partlythrough a neural reflex stimulated by sensory input to the penis, andterminating in smooth and striated muscle contractions that produceseminal emission and expulsion. Segraves hypothesized that increasedserotoninergic activation may be associated with orgasmic inhibition(Arch. Gen. Psychiatry., 46:275-284 (1989)) and reports that ejaculationseems to be mediated by alpha-receptor activation, presumably at aperipheral level with cholinergic fibers playing a modulatory role.Serotoninergic system involvement in ejaculation could occur at thelevel of the brain or spinal cord.

Several psychiatric drugs have been reported to have side effects ofinhibiting ejaculation. Thus, oral pharmacotherapy for prematureejaculation using tricyclic antidepressants or certain selectiveserotonin re-uptake inhibitor drugs has been studied as an alternativeto behavioral therapy (See, e.g., Merck Manual of Medical Information at421-422, Home Edition, Merck Research Laboratories (1997)). Open-labeland controlled studies have reported that these compounds increaseintravaginal ejaculatory latency effectively while avoiding side effectsin subjects with premature ejaculation.

For example, U.S. Pat. No. 5,672,612 discloses amorphous paroxetinehydrochloride-ethanol compositions for use as a therapeutic agent forpremature ejaculation. This reference also reports that sexualdysfunction typically associated with antidepressants, including delayedand completely abolished ejaculation, has been the subject of numerouscase reports, studies, and articles. See, e.g., Depression, 2:233-240(1994/1995); J. Clin. Psychiatry, 54:209-212 (1993); J. Clin.Psychopharmacol, 3:76-79 (1983). SSRI antidepressants seem to be a safetreatment option for patients with premature ejaculation, particularlyin cases with failed psychological treatment, although otheranti-anxiety drugs, such as chlordiazepoxide (LIBRIUM™) and diazepam(VALIUM™) are not suitable for the treatment of premature ejaculation.See also Clin. Neuropharmacology, 20(5):466-471 (1997) (treatment ofpremature ejaculation with fluoxetine) and Clin. Neuropharmacology,20(3):210-214 (mianserin for treatment of sexual dysfunction induced bySSRIs).

U.S. Pat. No. 5,151,448 discloses the chronic administration offluoxetine, preferably orally, in an amount in the range of about 5 mgto about 80 mg per day, preferably about 20 mg per day for the treatmentof premature ejaculation. The compositions are administered for a timeperiod of at least about 3 months, preferably for at least about 6months. In some instances, fluoxetine is administered chronically aslong as the patient remains sexually active.

U.S. Pat. No. 5,276,042 discloses the chronic administration ofparoxetine, preferably orally, in an amount in the range of about 3 mgto about 30 mg per day, preferably about 10 mg per day for the treatmentof premature ejaculation. The compositions are administered for a timeperiod of at least about 3 months, preferably for at least about 6months. In some instances, paroxetine is administered chronically aslong as the patient remains sexually active.

U.S. Pat. No. 5,597,826 discloses the administration of sertraline andan agonist or antagonist of the serotonin 1 (5-HT1) receptor and the useof such compositions for treating or preventing a condition selectedfrom a large list of disorders including sexual dysfunction, such aspremature ejaculation. These compositions are disclosed to beadministered daily, for example, one to four times daily.

McMahon reports that 37 potent men with premature ejaculation weretreated with 50 mg oral sertraline and placebo in a controlledrandomized single-blind crossover trial. Chronic open label treatmentwas continued in 29 patients that achieved an increase in ejaculatorylatency over pretreatment levels with active drug. McMahon, J. Urology,159(6):1935-1938 (1998). McMahon concluded that sertraline appeared tobe a useful and well tolerated oral treatment for premature ejaculationafter 1 to 2 weeks, with several patients maintaining that control afterchronic treatment for several months.

U.S. Pat. Nos. 5,770,606 and 5,624,677 disclose psychogenic impotence orerectile dysfunction that can be identified in patients and treated,without substantial undesirable side effects, by sublingualadministration of apomorphine dosage forms to maintain a plasmaconcentration of no more than about 5.5 nanograms per mL.

Certain selective serotonin re-uptake inhibitors have been reported asbeing useful for various indications. For example, U.S. Pat. No.5,135,947 discloses 1-phenyl naphthalonyloxypropanamines and methods ofusing the same for treating a variety of disorders that have been linkedto decreased neurotransmission of serotonin in mammals, includingobesity, depression, alcoholism, pain, memory loss, anxiety, smoking,and the like.

The above-discussed references primarily concern the chronicadministration of therapeutic agents for the treatment of prematureejaculation, but do not discuss administration on an as-needed basis. Asdiscussed above, treatment of premature ejaculation can involveadministration of certain selective serotonin reuptake inhibitors, suchas fluoxetine, paroxetine, or sertraline, to delay ejaculation. Thistype of drug works by increasing the amount of serotonin in the body andcan be administered daily (Merck Manual ofMedical Information at421-422, Home Edition, Merck Research Laboratories (1997)).

Paick et al. recently reported that self-therapy with sertraline tabletswas investigated by chronic administration followed by as-neededadministration on the day of intercourse. Paick, J. S., et al., J.Urology, 159(S5):241 (June, 1998).

This study was conducted with 24 males for six weeks, and the authorsreported that 50 mg doses were administered for 2 weeks followed by selftherapy with 50 mg or 100 mg of sertraline as-needed at 5 p.m. intreatment of premature ejaculation. The authors concluded that suchtherapy could possibly be as attractive as self-injection therapy in thetreatment of erectile dysfunction.

McMahon and Touma, J. Urol., 161:1826-1839 (1999) showed in 26 patientssuffering from premature ejaculation that prn dosing with a 20 mgparoxetine tablet 3-4 hours prior to intercourse resulted in astatistically significant increase in ejaculatory latency in the secondthrough fourth weeks of 10 paroxetine treatment but not in the firstweek, indicating that 1-2 weeks of priming doses of paroxetine arerequired. Frequency of intercourse was significantly increased onlyafter 3 weeks of prn paroxetine therapy.

In a subsequent paper, McMahon and Touma, International J. ImpotenceResearch, 11:241-246 (1999), showed that 20 mg prn paroxetine improvedejaculatory latency in only 42% of their patients and the increase inejaculatory latency was only reported as being statistically significantafter 4 weeks of treatment, again indicating the need for “primingdoses” of paroxetine. In addition, 37% of patients that initially showedimprovement in ejaculatory latency with continuous dosing of paroxetinesubsequently lost benefit after switching to prn dosing. Similarly,Salem, et al., J. Urol., 163(S4), 197 (2000), showed that 100% ofpatients that initially showed improvement in ejaculatory latency withcontinuous dosing of fluoxetine subsequently lost benefit afterswitching to prn dosing.

Proper treatment of premature ejaculation involves not just inhibitingearly ejaculation, but in ensuring that the patient has increasedcontrol over the timing of the ejaculation. The available options fortreating premature ejaculation also typically require daily dosage tomaintain suitable plasma levels. The daily or chronic use ofconventional SSRIs and related compounds for such therapy may result inadverse effects expected with high or continuing dosages of suchcompounds. In addition, chronic or daily administration of conventionalSSRIs is a burdensome requirement on the patient. Furthermore, thelatency period, from time of dosing to engaging in sexual activity,associated with conventional SSRIs is another hurdle which the patientmust deal with. Finally, not experiencing benefit from a drug with asingle, or the first, administration of drug is also burdensome. It isthus desired to find a compound and method for sexual dysfunctiontherapy, in particular, to provide increased control over ejaculatorytiming. In particular, it is desired to achieve the beneficialtherapeutic effect of preventing, treating, or managing sexualdysfunction while reducing or avoiding adverse effects associated withthe present protocols for administration of sexual dysfunction therapy.In particular, it is desirable to consistently achieve the maximumtherapeutic response within a convenient time frame followingadministration of a drug therapy immediately before to 4 hours on anas-needed basis to allow a patient to coordinate drug therapy with thetiming of intercourse following a single, or the first, dose.

SUMMARY OF THE INVENTION

The invention encompasses methods and compounds employing as neededdosing, also known as pro re nata dosing (referred to herein as “prndosing”), to prevent, treat, and manage sexual dysfunction therapy.Without wishing to be bound by theory, it is believed that these methodsand compounds provide therapy by accomplishing at least one of thefollowing: increasing the effect of monoamines in the mammal, increasingserotonin in the mammal, or inhibiting or avoiding reuptake of serotonininto nerve terminals in the mammal. Prn dosing reduces and/or avoidsadverse effects that can occur with chronic therapy of a therapeuticagent. Thus, the methods of preventing, treating, or managing sexualdysfunction comprise administering a therapeutically effective amount ofthe active agent to a patient in need of therapy immediately prior to,to about 12 hours prior to, the patient's anticipated sexual activityaccording to the invention. Preferably a therapeutically effectiveamount of the active agent is administered to a patient in need oftherapy immediately prior to, to about 10 hours prior to, the patient'santicipated sexual activity, more preferably immediately prior to, toabout 8 hours prior to, the patient's anticipated sexual activity, andmost preferably immediately prior to, to about 4 hours prior to, thepatient's anticipated sexual activity. In addition, a therapeuticallyeffective amount of the active agent can be administered to a patient inneed of therapy immediately prior to the patient's anticipated sexualactivity. Thus, the present invention eliminates the need for chronic ordaily administration of the active agent prior to anticipated sexualactivity.

Typically, the patient is a mammal, such as a dog, horse, rat, mouse, orhuman, but in particular, the patient is a human. In a preferredembodiment, the human is male with or at risk of sexual dysfunction,such as premature ejaculation.

One embodiment of the present invention is a method of treating ormanaging sexual dysfunction in a mammal in need of treatment whichcomprises administering on an as-needed basis to the mammal atherapeutically effective amount of a rapid-onset selective selectiveserotonin reuptake inhibitor. An example of a rapid-onset selectiveserotonin reuptake inhibitor is dapoxetine or a pharmaceuticallyacceptable salt thereof. As used herein the term “dapoxetine” refers tothe compound of the following formula.

which is also referred to as(S)-(+)-NN-Dimethyl-1-phenyl-3-(1-naphthalenyloxy)propanamine or as(S)-(+)-N,N-Dimethyl-α-[2-(1-naphthalenyloxy)ethyl-benzenemethanamine.It is understood by one of ordinary skill in the art that the method ofthe present invention includes the administration of a rapid-onsetselective serotonin reuptake inhibitor, such as dapoxetine as the freebase or as a pharmaceutically acceptable salt thereof, such as the HClsalt.

The embodiment preferably encompasses the treatment, prevention, and/ormanagement of such disorders using a single unit dosage form thatcontains dapoxetine, or a pharmaceutically acceptable salt thereof. Themethods of administering dapoxetine, or a pharmaceutically acceptablesalt thereof, are also useful in combination with an additionaltherapeutic agent, such as a conventional selective serotonin reuptakeinhibitor (as used herein the term “SSRI” refers to selective serotoninreuptake inhibitor) for the treatment, prevention, or management ofsexual dysfunction, such as premature ejaculation. The inventionencompasses the treatment, prevention, and/or management of sexualdysfunction and the symptoms thereof using dapoxetine. The inventionpreferably encompasses the treatment, prevention, and/or management ofsuch disorders using a single unit dosage form that contains dapoxetine,or a pharmaceutically acceptable salt thereof. However, it should berecognized that combination therapy by separate administration of thecompositions of the invention and an additional therapeutic agent, suchas another SSRI, is also contemplated. The methods and compositionsdescribed herein are believed to provide superior or improved therapyover prior art methods and compositions involving paroxetine,fluoxetine, venlafaxine, fluvoxamine, or sertraline in the absence ofdapoxetine, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating or managingsexual dysfunction in a mammal in need of treatment which comprisesadministering on an as-needed basis to the mammal a therapeuticallyeffective amount of a rapid-onset selective serotonin reuptakeinhibitor.

The present invention provides an improvement in flexibility of timingwith regard to when the therapeutically effective amount of therapid-onset selective serotonin reuptake inhibitor is taken in relationto the patient's participation in sexual activity, and thus, representsan improvement in the dosing schedule.

The present invention also provides an unexpected benefit with prndosing with dapoxetine over either prn dosing or continuous dosing withnon-rapid onset SSRIs, such as paroxetine, fluoxetine, and sertraline,in that the improvement in ejaculatory latency with prn dosing withdapoxetine occurs after the very first dose or a single dose.

The present invention also shows an improvement in the ability of prndosed SSRIs, preferably dapoxetine, to treat the full range of PEpatients, such as those who consider themselves severe (see tables 13aand 13b) or moderate (see tables 14a and 14b), and patients who have abaseline ejaculatory latency of less than one minute (see tables 10a and10b) or less than two minutes (see tables 11a and 11b). Dapoxetine alsoincreased ejaculatory latency in patients with baseline latenciesgreater than or equal to one minute (see tables 16a and 16b) or greaterthan or equal to two minutes (see tables 15a and 15b). This latter dataestablishes that administration of a rapid-onset SSRI would be ofbenefit to a male who does not suffer from premature ejaculation per se,but still wishes to prolong ejaculation.

The present invention provides additional benefit in allowingadministration of a therapeutically effective dose of a rapid-onsetSSRI, without causing accumulation of the drug when administered on adaily basis, through the drug's demonstration of a short half-life. Anexample of a rapid-onset SSRI with a short half-life is dapoxetine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows rapid-onset to reach peak plasma concentration followed byrapid metabolism (i.e. short half-life) in 20 volunteers who had taken adose of 40 mg dapoxetine at time zero of the 14th day of daily dosing.

FIG. 2 depicts the ejaculatory latency change in minutes vs. time afterdosing for placebo, 20 mg Dapoxetine, and 40 mg dapoxetine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention represents an improvement in overall therapyrelative to sexual dysfunction treatment technology presently available.

According to another aspect, the present invention provides the use of arapid-onset selective serotonin reuptake inhibitor, or apharmaceutically acceptable salt thereof, on an as-needed basis, for themanufacture of a medicament for treatment or management of sexualdysfunction.

According to yet another aspect, the present invention provides the useof a rapid-onset selective serotonin reuptake inhibitor, or apharmaceutically acceptable salt thereof, on an as-needed basis, fortreatment or management of sexual dysfunction.

The present invention further provides an article of manufacturecomprising packaging material and a pharmaceutical agent containedwithin said packaging material, wherein said pharmaceutical agent iseffective for treating premature ejaculation in a human male, andwherein said packaging material comprises a label which indicates thatsaid pharmaceutical agent can be used for treating premature ejaculationin a human male, and wherein said pharmaceutical agent comprises arapid-onset selective serotonin reuptake inhibitor or a pharmaceuticallyacceptable salt thereof.

The invention encompasses methods of preventing, treating, or managingsexual dysfunction in a mammal in need of therapy by administeringas-needed a therapeutically effective amount of a rapid-onset selectiveserotonin reuptake inhibitor, or a pharmaceutically acceptable saltthereof. A rapid-onset selective serotonin reuptake inhibitor isadministered to a mammal to, for example, increase the effect ofmonoamines, increase or enhance the effects of serotonin, and/or toinhibit or avoid the reuptake of serotonin into nerve terminals. Inparticular, the invention encompasses compounds and methods ofadministering as-needed a therapeutically effective amount of arapid-onset selective serotonin reuptake inhibitor, or apharmaceutically acceptable salt thereof, to a human in need of therapyto prevent, treat, or manage sexual dysfunction. A suitable rapid-onsetselective serotonin reuptake inhibitor of the present invention isdapoxetine. The invention is discussed in more detail below. For clarityof discussion, the specific example of dapoxetine is used herein toexemplify the use of rapid-onset selective serotonin reuptake inhibitorswith the present invention. The present invention also includesrapid-onset selective serotonin reuptake inhibitors that are shortacting selective serotonin reuptake inhibitors.

The present invention includes use of dapoxetine, in particular (a)(+)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine, or apharmaceutically acceptable salt thereof; (b)(S)-(+)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine(dapoxetine), or a pharmaceutically acceptable salt thereof; and (c)(R)-(−)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine, or apharmaceutically acceptable salt thereof, as well as any activemetabolites thereof. In particular, the active metabolites include, butare not limited to, mono desmethyl dapoxetine and di-desmethyldapoxetine. Typically, the compound administered will include only oneof these alternative forms, but may include more than one in varyingamounts.

As used herein the terms “Me”, “Et”, “Pr”, “EtOAc”, “THF”, and “DMF”refer to methyl, ethyl, propyl, ethyl acetate, tetrahydrofuran anddimethylformamide respectively.

As used herein the term “sexual activity” refers to an activityinvolving sexual arousal wherein the patient desires to avoid sexualdysfunction, such as premature ejaculation. Examples of sexual activityare intercourse, masturbation, sexual intercourse, and the like. Sexualintercourse is preferred.

As used herein the term “sexual arousal” refers to engorgement of asexual organ. Examples of sexual organs are the penis and clitoris.

As used herein the term “engorgement” refers to an increase in bloodflow to a sexual organ.

As used herein the term “intercourse” refers to physical stimulationbetween individuals that involves the genitalia of at least one person,such as intromission.

As used herein the term “intromission” refers to the insertion or periodof insertion of the penis into an orifice. An example of an orifice isthe vagina.

As used herein the term “a rapid-onset selective serotonin reuptakeinhibitor” refers to a drug with a pharmacokinetic profile wherein Tmaxis consistently less than about 4 hours. In alternative embodiments, “arapid-onset selective serotonin reuptake inhibitor” refers to a drugwith a pharmacokinetic profile wherein Tmax is consistently less thanabout 3 hours or consistently less than about 2 hours. Dapoxetine is anexample of a rapid-onset selective serotonin reuptake inhibitor.

As used herein the term “a short acting selective serotonin reuptakeinhibitor” refers to a drug with a pharmacokinetic profile whereinT_(1/2) is less than about 20 hours. In alternative embodiments, “ashort acting selective serotonin reuptake inhibitor” refers to a drugwith a pharmacokinetic profile wherein T_(1/2) is less than about 13hours or less than about 7 hours.

The term “racemic” as used herein, means a mixture of the (R) and (S)enantiomers of a compound where the (R) and (S) enantiomers are presentin approximately a 1:1 ratio.

The term “substantially free of its (R) stereoisomer” as used herein,means for example, that the compound contains a significantly greaterproportion of dapoxetine in relation to its (R) stereoisomer. In apreferred embodiment of the present invention, the compound contains atleast about 90% by weight of dapoxetine and about 10% by weight or lessof its (R) stereoisomer. In a more preferred embodiment of the presentinvention, the term “substantially free of its (R) stereoisomer” as usedherein, means that the compound contains at least about 95% by weight ofdapoxetine and about 5% by weight or less of its (R) stereoisomer. In amost preferred embodiment, the term “substantially free of its (R)stereoisomer” as used herein, means that the compound contains at leastabout 99% by weight of dapoxetine and about 1% or less of its (R)stereoisomer. In a most especially preferred embodiment, the term“substantially free of its (R) stereoisomer” as used herein, means thatthe compound contains nearly 100% by weight of dapoxetine.

The term “substantially free of its (S) stereoisomer” as used herein,means for example, that the compound contains a significantly greaterproportion of(R)-(−)N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine inrelation to its (S) stereoisomer. In a preferred embodiment of thepresent invention, the compound contains at least about 90% by weight of(R)-(−)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine andabout 10% by weight or less of its (S) stereoisomer. In a more preferredembodiment of the present invention, the term “substantially free of its(S) stereoisomer” as used herein, means that the compound contains atleast about 95% by weight of(R)-(−)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine andabout 5% by weight or less of its (S) stereoisomer. In a most preferredembodiment, the term “substantially free of its (S) stereoisomer” asused herein, means that the compound contains at least about 99% byweight of(R)-(−)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine andabout 1% or less of its (S) stereoisomer. In a most especially preferredembodiment, the term “substantially free of its (S) stereoisomer” asused herein, means that the compound contains nearly 100% by weight of(R)-(−)-N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine.

Dapoxetine and its pharmaceutically acceptable salts can be readilyprepared by procedures well known to those of ordinary skill in the art.See for example U.S. Pat. No. 5,135,947, issued Aug. 4, 1992 thedisclosure of which is incorporated herein by reference. In addition,for preparation of various useful intermediates of dapoxetine, see U.S.Pat. No. 5,292,962, issued Mar. 8, 1994 the disclosure of which isincorporated herein by reference.

In one embodiment of the present invention, a rapid-onset selectiveserotonin reuptake inhibitor or a pharmaceutically acceptable saltthereof can be administered to an animal in combination with a compoundcapable of increasing or enhancing the effect of monoamines or serotoninin the mammal. Preferred monoamine-increasing compounds include, but arenot limited to, amitriptyline (ELAVIL™ and VANATRIP™), amitriptyline andchlordiazepoxide (LIMBITROL™), amitriptyline and perphenazine (ETRAFON™and TRIAVIL™), amoxapine (ASENDIN™), clomipramine (ANAFRANIL™),citalopram (CELEXA™), dapoxetine, desipramine (NORPRAMIN™ andPERTOFRANE™), doxepin (ADAPIM™, SINEQUAN™, XEPDIN™, and ZONALON™),duloxetine, fluoxetine (PROZAC™), fluvoxamine (LUVOX™), imipramine(JANIMINE™, TOFRANIL™, and TOFRANIL-PM™), isocarboxazid (MARPLAN™),mirtazapine (REMERON™), nortriptyline (PAMELOR™), paroxetine (PAXIL™),phenelzine (NARDIL™), protriptyline (VIVACTIL™), refazodone (SERZONE™),selegiline (ALZENE™, CAREBEX™, DEPRENYL™, and ELDEPRYL™), sertraline(ZOLOF™), tranylcypromine (PARNATE™), trazadone (DESYREL™), trimipramine(SURMONTIL™), and venlafaxine (EFFEXOR™).

It should also be recognized for all embodiments herein that combinationtherapy by separate administration of the compounds of the invention andan additional therapeutic agent, such as one or more drugs (e.g.,yohimbine) for a second, different sexual dysfunction is alsocontemplated.

The various compounds enumerated above with a tradename are generallycommercially available. The remaining compounds may be readily preparedor obtained by those of ordinary skill in the pharmaceutical art. Forexample, one of ordinary skill in the art is readily able to synthesizedapoxetine, or a pharmaceutically acceptable salt thereof, as well asmetabolites or the optically pure stereoisomers or salts thereof, foruse in the compounds and methods of the invention, such as by followingthe teachings of U.S. Pat. No. 5,135,947. See also W. J. Wheeler, etal., “A Chiral Synthesis of Dapoxetine Hydrochloride, a SerotoninRe-uptake Inhibitor, and its ¹⁴C Isotopomer,” J. Labeled CompoundsRadiopharmaceuticals, 31(4):305-315 (1992).

The terms “composition(s),” “active agent(s),” and “compound(s),” asused herein, each encompass: (a) composition(s) to increase the effectof monoamines; (b) composition(s) to increase serotonin in the mammal;(c) composition(s) that inhibit or avoid the reuptake of serotonin intonerve terminals in the mammal; and (d) serotonin-selective re-uptakeinhibitor(s); or a pharmaceutically acceptable salt thereof. The terms“composition(s),” “active agent(s),” and “compound(s)” also include anyoptically pure isomer, or a pharmaceutically acceptable salt thereof, aswell as any active metabolite, or a pharmaceutically acceptable saltthereof, of the above-noted compound(s).

The term “additional therapeutic agent(s),” as used herein, refers tothe use of compounds that may be used in addition to the compound toprevent, treat, or manage sexual dysfunction in a patient in need oftherapy. For example, yohimbine or nitric oxide may be used for erectiledysfunction therapy in addition to a compound as discussed hereinaccording to the invention. Other suitable additional therapeutic agentsinclude, but are not limited to, eicosanoids, such as alprostadil, andphosphodiesterase inhibitors, such as sildenafil citrate (VIAGRA™) andIC 351.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds disclosed herein which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are known as acid addition salts. Pharmaceutically acceptablesalts also include compounds that have been formulated to have a Tmax ofless than about 4 hours.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenyisulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesuffonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that the above salts may form hydratesor exist in a substantially anhydrous form.

The pharmaceutical compounds used in the methods of the presentinvention, which are sterile where appropriate, include any of theabove-listed compounds, or a pharmaceutically acceptable salt thereof,as the active ingredient. The compounds may also contain apharmaceutically acceptable carrier or excipient, and optionally, othertherapeutic ingredients.

The compounds for use in the methods of the present invention caninclude suitable excipients or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like. Examples of suchexcipients include water, saline, Ringer's solution, dextrose solution,Hank's solution, and other aqueous physiologically balanced saltsolutions. Nonaqueous vehicles, such as fixed oils, sesame oil, ethyloleate, or triglycerides may also be used. Other useful formulationsinclude suspensions containing viscosity-enhancing agents, such assodium carboxymethylcellulose, sorbitol, or dextran. Excipients can alsocontain minor amounts of additives, such as substances that enhanceisotonicity and chemical stability. Examples of buffers includephosphate buffer, bicarbonate buffer and Tris buffer, while examples ofpreservatives include thimerosal, o-cresol, formalin and benzyl alcohol.Standard formulations can either be liquid injectables or solids, whichcan be taken up in a suitable liquid as a suspension or solution forinjection. Thus, in a non-liquid formulation, the excipient can comprisedextrose, human serum albumin, preservatives, etc., to which sterilewater or saline can be added prior to administration.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, caplets, cachets, patches, gel caps, syrups,elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes,plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols,and the like.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or non-aqueous techniques.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered to facilitate as-neededadministration by controlled release means or delivery devices that arewell known to those of ordinary skill in the art, such as thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; and 5,733,566, the disclosures of which are eachincorporated herein by express reference thereto. These pharmaceuticalcompositions can be used to provide slow or controlled-release of one ormore of the active ingredients therein using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or the like, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, may be readily selected for usewith the pharmaceutical compounds and methods of the invention. Thus,single unit dosage forms suitable for oral administration, such astablets, capsules, gelcaps, caplets, and the like, that are adapted forcontrolled-release are encompassed by the present invention. The term“controlled-release formulation(s),” as used herein, means a formulationadapted to provide extended release of the active ingredient(s) duringthe need for therapy. For example, but in no way intended to limit theinvention, a controlled-release formulation according to the inventionmight release active ingredient(s) over a 2 to 8 hour period of time.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts.

Ideally, the use of an optimally designed controlled-release preparationin medical treatment according to the invention is characterized by aminimum of drug substance being employed to cure or control thecondition during the need for therapy. Advantages of controlled-releaseformulations according to the invention may include: 1) activity of thedrug that is extended for the duration of the need for therapy; 2)reduction of peak plasma concentration of the active ingredient(s); and3) increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effect,and gradually and continually release of other amounts of drug tomaintain this level of therapeutic effect over a period of timesufficient to provide the as-needed therapy. In order to maintain thisconstant level of drug in the body while needed for therapy, the drugmust be released from the dosage form at a rate that will replace theamount of drug being metabolized and excreted from the body. The drugmust also be released at a sufficient rate to facilitate absorption intothe bloodstream during the need for therapy.

The controlled-release of an active ingredient may be stimulated byvarious inducers, for example pH, temperature, enzymes, water, or otherphysiological conditions or compounds. The term “controlled-releasecomponent,” as used herein, means a compound or compounds, including,but not limited to, polymers, polymer matrices, gels, permeablemembranes, liposomes, microspheres, or the like, or a combinationthereof, that facilitates the controlled-release of the activeingredient as-needed for therapy.

In addition, it is understood that the compounds of the presentinvention may be administered as rapidly disintegrating or dissolvingpharmaceutical dosage forms which are readily prepared by one ofordinary skill in the art. Such formulations are useful, for example,for human patients who have difficulty swallowing conventional tabletsor capsules, and are also useful for the sublingual and buccaladministration of drugs.

Observations from the final analyses of the study cited in the examplesection allow one to predict that a non-rapid onset SSRI formulated toprovide rapid-onset selective serotonin reuptake inhibition would beexpected to provide substantial benefit over current formulations ofnon-rapid onset SSRIs. Thus, a further embodiment of the presentinvention is the delivery of a non-rapid onset SSRI, such as fluoxetine,paroxetine, or sertraline, in a rapid release formulation.

For example, freeze-dried or lyophilized dosage forms are generallyknown to rapidly dissolve or disintegrate in the mouth. These formsconsist of a porous matrix of a water-soluble or water-dispersiblecarrier material which is impregnated with a unit dose of the activecompound. These dosage forms are prepared by first adding the activecompound to a solution comprising the carrier material and a suitablesolvent, typically water. The resulting composition is then subjected toa freeze drying procedure whereby the solvent sublimes under a highvacuum.

In addition, U.S. Pat. No. 4,866,046, issued Sep. 12, 1989, describes anaspirin tablet, for example, that rapidly dissolves in the oral,preferably sublingual, cavity within 2-60 seconds. This tablet providesrapid absorption of aspirin from the saliva into the blood stream. Thesublingual tablet is prepared by compressing into slugs a mixture ofstarch (10% moisture), acetylsalicylic acid, flavor and sweetener. Theslugs are then ground (14-16 Mesh size) and recompressed into tablets.An amino acid may also be used with the aspirin for its solubilizing anda taste-neutralizing effects.

U.S. Pat. No. 5,082,667, issued Jan. 21, 1992, discusses a tablettriturate dosage that dissolves quickly in the buccal cavity. The formincludes a porous, cementatory network of a water-soluble butethanol-insoluble carbohydrate, which contains discrete particles of theactive compound that have been coated with a triglyceride coating. Thediscrete particles are prepared by suspending the active ingredient inmolten triglyceride. The discrete particles are mixed with thecarbohydrate and a temporary liquid binder to form a damp mass. The massis then shaped into a tablet and dried to form the tablet triturate.This tablet triturate method is limited, however, to active compoundsthat are not sensitive to the melting temperature of the triglyceride.

Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form, such as powder or granules,optionally mixed with a binder, lubricant, inert diluent, surface activeor dispersing agent. Molded tablets may be made by molding, in asuitable machine, a mixture of the powdered compound moistened with aninert liquid diluent.

The administration of these compositions in the methods of the presentinvention may be either concurrent or sequential, e.g., a rapid-onsetselective serotonin reuptake inhibitor, or a pharmaceutically acceptablesalt thereof, may be administered as a combination (a single unitdosage), or concurrently but separately, with one or more additionaltherapeutic agents, such as one or more drugs for erectile dysfunctionor low libido, for the prevention, treatment, or management of sexualdysfunction. The compounds of the invention may also be provided by thesequential administration of one of the compounds discussed above andone or more additional therapeutic agents suitable for the prevention,treatment, or management of a sexual dysfunction in any possible order.The compositions administered in each of these methods may beconcurrent, sequential, or in any combination of concurrent and/orsequential.

The terms “as-needed,” “as-needed basis,” “prn,” and “prn dosing,” asused herein, mean administering a therapeutically effective amount of arapid onset selective serotonin reuptake inhibitor according to theinvention at a time interval sufficient to provide an improvedtherapeutic profile, i.e., improved therapy, in the prevention,treatment, or management of sexual dysfunction while avoiding primingdoses, chronic administration, and/or overdosing. As used herein, theterm “therapeutically effective amount,” means the amount of a rapidonset selective serotonin reuptake inhibitor or a pharmaceuticallyacceptable salt thereof, that provides a therapeutic benefit in thetreatment, prevention, or management of one or more sexual dysfunctionsor the symptoms of the one or more sexual dysfunctions. The term “sexualdysfunction,” as used herein, includes, but is not limited to, prematureejaculation, retarded ejaculation (male), inhibited orgasm (female), lowsexual desire, sexual aversion, dyspareunia, and vaginismus. Inparticular, sexual dysfunction means premature ejaculation. The term“premature ejaculation,” as used herein, means intravaginal ejaculationlatency of less than 2 minutes that has occurred in greater than 50% ofintercourse for at least the previous 6 months. The term is also used inaccordance with DSM IV to mean: (1) persistent or recurrent ejaculationwith minimal sexual stimulation before, on, or shortly after penetrationand before the person wishes it, which must account for factors thataffect duration of the excitement phase, such as age, novelty of thesexual partner or situation, and recent frequency of sexual activity;(2) the disturbance causes marked distress or interpersonal difficulty;and (3) the premature ejaculation is not due exclusively to the directeffects of a substance (e.g., withdrawal from opioids).

One embodiment of the present invention is prn dosing of a rapid-onsetselective serotonin reuptake inhibitor, or a pharmaceutically acceptablesalt thereof, prior to sexual activity. A preferred method includes prndosing of a rapid-onset selective serotonin reuptake inhibitor fromimmediately prior to, to about 12 hours prior to, sexual activity.

A more preferred method includes prn dosing immediately prior to, toabout 10 hours prior to, sexual activity. A more preferred methodincludes prn dosing immediately prior to, to about 8 hours prior to,sexual activity. A most especially preferred method includes prn dosingimmediately prior to, to about 4 hours prior to, sexual activity.

Those of ordinary skill in the art are well aware of a suitable timeinterval for dosing purposes as discussed herein, which may depend onother therapeutic compositions being taken by the patient. By way ofexample, and in no way intended to be limiting, a suitable time intervalmight be about 1 to 4 hours prior to the need for therapy, but not morethan once per day.

The amount of a dose of a rapid-onset selective serotonin reuptakeinhibitor, or a pharmaceutically acceptable salt thereof, in prn dosingis an amount suitable for management of a disorder or condition. Theamount will vary with the severity of the condition to be treated andthe route of administration.

The dose and dose frequency will also vary according to the age, bodyweight, and response of the individual patient. A suitable dose rangecan be readily determined by one of ordinary skill in the art. Ingeneral, the total dose for a rapid-onset selective serotonin reuptakeinhibitor, or a pharmaceutically acceptable salt thereof, for theconditions described herein, ranges from about 0.001 mg to about 350 mg,preferably from about 0.01 mg to about 200 mg, more preferably fromabout 0.01 mg to about 120 mg, and most especially preferred about 1 mgto about 80 mg, administered in single or divided doses as needed. Thesedosages are preferably adapted for self-administration as needed by thepatient.

It is further recommended that patients aged over 65 years, and thosewith impaired renal or hepatic function, initially receive low doses,and that they then be titrated based on individual response(s) or bloodlevel(s). It may be necessary to use dosages outside these ranges insome cases, as will be apparent to those lo skilled in the art. Further,it is noted that the clinician or treating physician will know how andwhen to adjust, interrupt, or terminate therapy in conjunction withindividual patient response.

EXAMPLES

The efficacy of a prn dosing method of the present invention can betested in a variety of ways. For example, a skilled artisan couldcompare responses with and without administration of a prn dose ofdapoxetine, or a pharmaceutically acceptable salt thereof, (within atime frame compatible with the pharmacokinetics of dapoxetine). Suitableresponses to compare include, for example, determining latency frominitiation of sexual activity until time of ejaculation with achronometer, by determining the number of pelvic thrusts associated withintercourse, by counting the number of times ejaculation occurs prior topenetration, or through the use of a question or series of questionsposed to the patients.

The efficacy of a prn dosing method with dapoxetine, or apharmaceutically acceptable salt thereof, can be determined, forexample, as follows. In vivo testing of human subjects can be conductedvia a double-blind, randomized, placebo-controlled safety and efficacystudy at 2 to 15 sites. To ensure 128 evaluable subjects, approximately168 subjects can be randomized to one of four treatments: placebo, 20 mgor 40 mg dapoxetine. The study can include a screening visit, a lead-inperiod of 4 weeks or less in which intercourse was attempted at least 4times, and a treatment period of 4 weeks or less in which intercoursewas attempted at least 4 times. Subjects should be healthy men at least18 years of age with a diagnosis of premature ejaculation.

Subjects should be instructed to take study medication (one dose is 2tablets of either placebo, 10 mg or 20 mg dapoxetine) within 1-3 hoursof anticipated sexual activity. Study medication is not taken more than1 time per day. Subjects can be stratified at the time of enrollment ina 1:1:1 ratio of placebo and 2 doses of dapoxetine. Efficacy ofdapoxetine, or a pharmaceutically acceptable salt thereof, can beassessed by comparing ejaculatory latencies recorded with a stopwatch bythe partner and recorded in an event log.

The patient-perceived-benefit of prn dosing method with dapoxetine, or apharmaceutically acceptable salt thereof, can be determined, forexample, through administration of a global satisfaction question, suchas,

“How would you complete the following statement?

The new bottle of medication that I received at my previous visit mademy premature ejaculation problem.

-   -   ______ much better    -   ______ better    -   ______ slightly better    -   ______ the same    -   ______ slightly worse    -   ______ worse    -   ______ much worse”

In addition, the patient-perceived-benefit of prn dosing method withdapoxetine, or a pharmaceutically acceptable salt thereof, can bedetermined, for example, through administration of a psychometricquality of life instrument, such as a premature ejaculationquestionnaire (PEQ).

Subjects should be healthy men at least 18 years of age with a diagnosisof premature ejaculation as defined by DSM IV. Subjects who meet theselection criteria can provide a medical history and have psychosexualand physical examinations at screening. Efficacy of dapoxetine, or apharmaceutically acceptable salt thereof, can be assessed by comparingejaculatory latencies recorded with a stopwatch by the partner andrecorded in an event log. Safety can be assessed by clinical laboratoryanalyses, vital signs, and adverse experience reports collectedthroughout the study. A physical examination, including chest x-ray andECG, can be performed at the final visit.

Each subject should comply with the following criteria, prematureejaculation as defined in the DSM IV or intravaginal ejaculation latencyover 2 minutes that occurred in over 50% of intercourse for at least theprevious 6 months, as noted by both Subject and Partner/Spouse. Criteriafor Premature Ejaculation should be as follows: (1) persistent orrecurrent ejaculation with minimal sexual stimulation before, on, orshortly after penetration and before the person wishes it. The clinicianmust take into account factors that affect duration of the excitementphase, such as age, novelty of the sexual partner or situation, andrecent frequency of sexual activity; (2) the disturbance causes markeddistress or interpersonal difficulty; and (3) the premature ejaculationis not due exclusively to the direct effects of a substance (e.g.,withdrawal from opioids).

Subjects in the study should be heterosexual male, at least 18 years ofage in a stable, monogamous, sexual relationship for at least 6 months.The Subject and Partner/Spouse should both agree to attempt at least 4vaginal intercourses between visit 1 and visit 2 (which can be no longerthan 4 weeks time) and 4 vaginal intercourses between visit 2 and visit3, visit 3 and visit 4, and visit 4 and visit 5 (none of which can belonger than 4 weeks time). The Subject and Partner should be capable ofunderstanding and complying with the protocol and both have understoodand signed the informed consent document. If Partner/Spouse is ofchildbearing potential (i.e., not postmenopausal or not surgicallysterile) and Subject is not sterile, Subject and/or Partner should usean acceptable form of birth control (condom, oral contraceptives).Subject and Partner should agree to use the same form of birth controlthroughout the study.

Subjects meeting any of the following criteria should be excluded fromthe study, any clinically significant abnormalities, history or presenceof cardiac or vascular disease, hypertension, hepatic, renal pulmonary,neurological or endocrinologic diseases, significantly abnormal ECG atscreening, a history of alcohol/drug abuse within previous 6 months;average consumption of more than 2 drinks per day, a presence of majorpsychiatric disorders (e.g., schizophrenia, depression), concurrenterectile dysfunction, urethritis, chronic prostatitus, pelvic surgery ortrauma/injury to spinal cord, positive hepatitis B surface antigen (HBsAg), HCV, or human immunodeficiency virus (HIV) test results, has aknown hypersensitivity to dapoxetine or other SSRIs, has received anyinvestigational drugs within the previous 30 days, is unwilling orunable to cooperate fully with the Investigator, is taking theanti-hypertensive drugs, guanethidine or reserpine, or has evidence ofany medical condition that would interfere with premature ejaculation,such as Subjects taking any of the medications within the stated washoutperiod listed below in Table 1. TABLE 1 Medications Medication/TreatmentWashout Period Over the counter cough/cold preparations  7 daysAntiepileptics (e.g., phenytoin) 30 days Antispasmodics (e.g.,procyclidine) 30 days Barbiturates (e.g., phenobarbital) 30 daysCimetidine 30 days Other Investigational Drugs 30 days Prescription orover the counter diet 30 days medications or treatments Sedatingantihistamines 30 days Warfarin-like compounds (e.g., Coumadin) 30 daysLithium 30 days Selective Serotonin Re-uptake Inhibitors 30 days [SSRIs](e.g., ZOLOFT, PAXIL, PROZAC] Tncyclicm Antidepressants (e.g., Coxefen,30 days Nortriptylene, Amitriptyline) Monoamine Oxidase Inhibitors[MAOls] 30 days (Nardil, Pamate, etc.) Antihypertensives: α-blockers;clonidine; α- 30 days methyl DOPA, or 13-blockers

Subjects can be stratified at the time of enrollment in a 1:1:1 ratio ofplacebo and 2 doses of dapoxetine. Both the Investigator and Subjectshould be blinded from study drug assignment.

Vital signs assessments include blood pressure, heart rate, respiration,and body temperature and these can be determined at Screening and visits2, 3, 4, and 5. Blood pressure and heart rate measurements can beobtained with the Subject recumbent and sitting. Oral body temperature(degrees Fahrenheit) may be measured as part of each set of vital signmeasurements specified above. Laboratory analysis of standard assays canbe done at Screening and visits 2, 3, 4, and 5. Patients can be givenevent logs and stopwatches at visit 1 to record the time studymedication is taken, when intercourse is attempted, and the ejaculatorylatency, defined as the time from intromission to ejaculation. Thepatient and partner can initial each event in the event log.Questionnaires should be administered at visits 1, 2, 3, 4, and 5 at theinvestigative site. Subjects can be given 6 doses of study drug (i.e.,12 capsules) at visit 2.

Subjects should self-administer the study medication within 1-3 hours ofanticipated sexual activity. The study drug should not be taken morethan one time per day. Dosing can be captured by the Subject in hisevent log. Dosing information in the Subject's event log can be comparedto the amount of drug left at visit 3.

Subjects cannot take any of the medications listed in the table in theExclusion Criteria section within the specified washout period. Subjectsshould not take new medications (i.e., medications started within 30days prior to study start or at some point during the study) or stoptaking any medications during the course of this study. Use of allmedications (over-the-counter, prescription, and herbal) can be recordedon the concomitant medication page of the case report form.

Comparisons can be made between absolute values for placebo-treatedversus each of the dapoxetine-treated groups.

Subjects can be required to attempt intercourse on at least 4 occasionsacross a maximum time period of 4 weeks during the lead-in period. After4 attempts at intercourse, the subjects should return for visit 2. Eventlogs should be collected, subject/partner global satisfaction recorded,and the quality of life questionnaire administered. The subject shouldbe randomized to one of 18 dosing regimens of placebo or dapoxetine (20or 40 mg pm). After 4-6 attempts at intercourse across a maximum timeperiod of 4 weeks, the subject should return for visit 3. Event logsshould be collected, subject/partner global satisfaction recorded, andthe quality of life questionnaire administered. The next dose of placeboor dapoxetine should then be distributed. After 4-6 attempts atintercourse across a maximum time period of 4 weeks, the subject shouldreturn for visit 4. This pattern can be repeated until the patient hasreceived placebo and both doses of dapoxetine.

Measures for “ejaculatory latency” and “number of thrusts prior toejaculation” should be recorded as the average of the 4-6 eventsrecorded in the event logs for that treatment period. Subjects whoejaculated prior to intromission should have a zero recorded for both“ejaculatory latency” and “number of thrusts prior to ejaculation.”“Measures for Subject and Partner satisfaction scores (globalimpression)” and “Subject and Partner ejaculatory (or sexual)quality-of-life questionnaire” for each treatment period should be basedon the score collected at the visit immediately following each treatmentperiod.

Capsules or tablets can be prepared that contain placebo, 10 mg or 20 mgdapoxetine. Two capsules or two tablets should be taken by a Subject 1-3hours prior to anticipated sexual activity. Other suitable oralformulations for the present invention are listed in Tables 2, 3, 4, 5,6 and 7. TABLE 2 Oral Formulation 5 mg 10 mg 20 mg Component capsulecapsule capsule Dapoxetine 5.0 10.0 20.0 Microcrystalline 90.0 90.0 90.0Cellulose Pre-gelatinized 100.3 97.8 82.8 Starch Croscarmellose 7.0 7.07.0 Magnesium 0.2 0.2 0.2 Stearate

The active ingredient (e.g., dapoxetine, or a pharmaceuticallyacceptable salt thereof) can be sieved and blended with the excipientslisted. The mixture can be filled into suitably sized two-piece hardgelatin capsules using suitable machinery and methods well known in theart. See Remington's Pharmaceutical Sciences, 16th or 18th Editions,each incorporated herein in its entirety by this reference. Other dosesmay be prepared by altering the fill weight and, if necessary, changingthe capsule size to suit. TABLE 3 Compressed Tablet Unit Dosage FormsComponent 2.5 mg tablet 5.0 mg tablet 20 mg tablet Dapoxetine 2.5 5.020.0 Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.397.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2Stearate

The active ingredient (e.g., dapoxetine, or a pharmaceuticallyacceptable salt thereof) can be sieved through a suitable sieve andblended with the excipients until a uniform blend is formed. The dryblend can be screened and blended with the magnesium stearate. Theresulting powder blend can then be compressed into tablets of desiredshape and size. Tablets of other strengths can be prepared by alteringthe ratio of the active ingredient to the excipient(s) or modifying thetable weight. TABLE 4 Tablets Quantity per Tablet in mg. Formula A B CActive Ingredient: 5.0 10.0 25.0 Dapoxetine Lactose BP 62.0 107.0 137.0Starch BP 20.0 20.0 25.0 Microcrystalline Cellulose 10.0 10.0 10.0Hydrogenated Vegetable Oil 1.5 1.5 1.5 Polyvinylpyrrolidinone 1.5 1.51.5 Compression Weight 100.0 150.0 200.0

The active ingredient (e.g., dapoxetine, or a pharmaceuticallyacceptable salt thereof) can be sieved through a suitable sieve andblended with the lactose until a uniform blend is formed. Suitablevolumes of water are added and the powders are granulated. After drying,the granules are then screened and blended with the remainingexcipients. The resulting granules are then compressed into tablets ofdesired shape. Tablets of other strengths can be prepared by alteringthe ratio of active ingredient to the excipient(s) or the compressionweight. TABLE 5 Tablets Quantity per Tablet in mg. Formula A B C ActiveIngredient: 5.0 10.0 25.0 Dapoxetine Lactose BP 48.5 93.5 83.5 Starch BP30.0 30.0 60.0 Pregelatinized Maize Starch BP 15.0 15.0 15.0 Magnesiumstearate BP 1.5 1.5 1.5 Compression Weight 100.0 150.0 540.0

The active ingredient (e.g., dapoxetine, or a pharmaceuticallyacceptable salt thereof) can be sieved through a suitable sieve andblended with lactose, starch, and pregelatinized maize starch until auniform blend is formed. Suitable volumes of water are added and thepowders are granulated. After drying, the granules are then screened andblended with the remaining excipients. The resulting granules are thencompressed into tablets of desired shape. Tablets of other strengths canbe prepared by altering the ratio of active ingredient to excipient(s)or compression weight. TABLE 6 Tablets Quantity per Tablet in mg.Formula A B C Active Ingredient: 5.0 10.0 25.0(R)-(—)-N,N-Dimethyl-1-phenyl-3- (1-naphthalenyloxy)-propanamine LactoseBP 48.5 43.5 78.5 Starch BP 30.0 30.0 30.0 Pregelatinized Maize StarchBP 15.0 15.0 15.0 Magnesium stearate BP 1.5 1.5 1.5 Compression Weight100.0 100.0 100.0

The active ingredient,(R)-(−)-N,N-Dimethyl-1-phenyl-3-(1-naphthalenyloxy)-propanamine, can besieved through a suitable sieve and blended with lactose, starch, andpregelatinized maize starch until a uniform blend is formed. Suitablevolumes of water are added and the powders granulated. After drying, thegranules are screened and blended with the remaining excipients. Theresulting granules are then compressed into tablets of desired shape.Tablets of other strengths can be prepared by altering the ratio ofactive ingredient to the excipient(s) or the compression weight. TABLE 7Composition of placebo, 10 mg Dapoxetine, 20 mg Dapoxetine, and 30 mgDapoxetine Capsules. 10 mg 20 mg 30 mg Ingredient Placebo CapsuleCapsule Capsule Dapoxetine HCI (mg) NA 11.351 22.702 34.053 Starch,pregelatinized, 223.31 211.959 200.608 189.257 NF (Starch 1500) (mg)Dimethicone, NF (mg) 1.69 1.69 1.69 1.69 (Dow Corning 360 Medical Fluid,350 cs) Total Fill Weight per 225 225 225 225 Capsule (mg)*The amounts of dapoxetine HCl are equivalent to the correspondingpotencies (10 mg, 20 mg, and 30 mg) of the free base, dapoxetine.

Table 7 provides an additional formulation for the placebo and the 10mg, 20 mg, and 30 mg capsules of dapoxetine. Dapoxetine HCl is blendedwith the excipients listed in Table 7 under conditions and usingtechniques well known to one of ordinary skill in the art. The mixtureis then filled into suitably sized hard gelatin capsules using suitablemachinery and methods well known in the art.

The Investigator can give the Subject 12 capsules of study drug at eachvisit beginning with visit 2 and ending with visit 4. Twelve capsulesshould be sufficient supply for the target of 4 attempts at intercourse(8 capsules) plus 2 planned, but aborted, attempts (4 “extra” capsules).At each subsequent visit, Subjects should return unused study medicationfrom the previous treatment period and can be given the next 12 capsules(containing a different dosage from the previous study periods) of studydrug. The Subject should be allowed a maximum of one dose (two capsules)per day. Drug administration should be recorded by the Subject in hisevent log. Investigator should maintain a dispensing and an inventoryrecord of all test articles during the study and should compare amountof study medication returned at these visits to drug administrationrecord in the Subject's event log. Any unused test articles should bereturned to the sponsor at the end of the study.

After first treatment period, patient can be crossed over to a differentdose of study medicine (placebo, 20 mg or 40 mg dapoxetine). After thesecond treatment period, patient can be crossed over to the final studymedicine (placebo, 20 mg or 40 mg dapoxetine).

Any suitable route of administration may be employed for providing amammal with an effective dosage of dapoxetine according to the methodsof the present invention. For example, oral, rectal, parenteral,epicutaneous, transdermal, subcutaneous, intramuscular, intranasal,sublingual, buccal, intradural, intraocular, intrarespiratory, or nasalinhalation and like forms of administration may be employed. Oraladministration is generally preferred due to ease of administration,particularly where self-therapy is administered by the mammal.

As used herein the terms “study drug” or “study medicine” refer toeither the placebo dose, the 20 mg dose of dapoxetine or the 40 mg doseof dapoxetine.

The results of an interim analysis of a randomized, double-blind, threeway crossover evaluation of two prn doses of dapoxetine (20 mg and 40mg) in the treatment of premature ejaculation (hereinafter referred toas “PE”) are disclosed in tables 8a and 8b. Each patient is assigned toreceive 4 to 6 administrations of each of the 3 study doses, in a randomorder, over 3 periods of not more than 4 weeks each. Interim analysis ofthe data was conducted following completion of the first treatmentperiod.

The study comprised 155 men, aged 19 to 60, presenting with PE asdefined in the DSM IV. All patients were involved in a stable monogamoussexual relationship of at least 6 months duration and reported a historyof intravaginal ejaculatory latency (hereinafter referred to as “EL”) ofless than 2 minutes in greater than half of their intercourseexperiences. History of significant cardiovascular disease orpsychiatric disorder, uncontrolled hypertension, erectile dysfunction,and substance abuse were criteria for exclusion.

During a lead-in period (maximum of 4 weeks), patients were asked torecord ejaculatory latency a minimum of 4 times. Latency is defined asthe time span, as measured by the patient's partner via a stopwatch,from vaginal intromission to ejaculation. At the completion of thelead-in period, patients were randomized to treatment with either 20 mgor 40 mg dapoxetine or placebo. Study medication was to be ingested 1 to3 hours prior to a planned intercourse event. The time study drug wastaken and time of intercourse was recorded in an event log. Patientswere instructed to attempt intercourse at least 4 times over the 4 weektreatment period and were issued a sufficient supply of medication tocomplete 6 attempts at intercourse. The outcome of each attempt (successof intromission and EL) was recorded in the event log initialed by thepatient and his partner. Patients returned to the study clinic for afollow-up visit after 4 to 6 attempts at intercourse were completed. Atvisits 4, 5, and 6 patients were asked to answer the Global SatisfactionQuestions and to complete the PEQ.

Of the 155 patients randomized, 145 completed the treatment period. 54patients were randomized to the placebo group, while 56 and 45 received20 mg or 40 mg dapoxetine respectively. Although patients were randomlyassigned to treatment sequences in blocks of 6, the imbalance in thenumber of patients randomized to each group was due to the randomdistribution of the 40 mg assignment to later allocations within theblocks. The intent-to-treat population was comprised of 143 patients,each of whom had baseline and follow-up data for analysis. Analysis ofEL was conducted on the 138 patients who had latency data at baselineand at least one post-medication event. The percentage of patients withdata sufficient for inclusion in the analysis of EL was lower in the 40mg group than in either of the other two groups. This difference may beattributable to the smaller size of the 40 mg group, such that eachpatient represents a greater percentage of the whole, rather than beinga function of the dose administered.

Patients across all three groups attempted intercourse followingingestion of study drug an average of 4.4 times. Mean ejaculatorylatency at baseline (the average of all recorded EL during the 4 weeklead-in period) was 18 seconds longer in the placebo group than ineither dapoxetine group. An EL evaluable patient was one who had both abaseline and a follow-up latency value. It is notable that 22.5%, 16.0%and 13.5% of EL evaluable patients in the placebo, 20 mg dapoxetine and40 mg dapoxetine groups respectively had mean baseline EL above 2minutes, with some recording mean values as high as 7 minutes.

Tables 8a and 8b provide summaries of the ejaculatory latency in minutesfor the baseline and follow-up respectively. TABLE 8a Baseline - 4-6Attempts at Intercourse Lead-in Dapoxetine Dapoxetine Dapoxetine Placebo20 mg 40 mg 20 & 40 mg N 51 patients 50 patients 37 patients 87 patient,Mean ± S.D.  1.6 ± 1.09  1.3 ± 0.91  1.3 ± 1.24 1.3 ± 1.06 (minutes)Range 0.2-5.6 0.1-4.2 0.0-7.0  0-7.0 (minutes)

TABLE 8b Follow-up - 4-6 Attempts at Intercourse Treatment DapoxetineDapoxetine Dapoxetine Placebo 20 mg 40 mg 20 & 40 mg N 51 patients 50patients 37 patients 87 patient, Mean ± S.D.  2.0 ± 1.48 2.3 ± 2.26  2.3± 2.19 2.3 ± 2.22 (minutes) LS Mean 1.74 2.41  2.52  NA (minutes) Range0.2-7.6 0.1-11.4 0.0-9.8 0.0-11.4 (minutes) P value v. NA 0.0340 0.02280.0103 placebo* NA represents “not applicable.”**LS represents “least squares,” and is the mean value with adjustmentfor differences in baseline and sample size.

As summarized in table 8b above, the mean ejaculatory latency for allintercourse events that followed ingestion of dapoxetine increased byone minute for both the 20 mg and 40 mg dapoxetine treatment groups,while EL increased only 24 seconds in the placebo group. When the dataare adjusted for sample size and baseline differences betweentreatments, the LS means are 1.74 minutes for placebo, 2.41 for the 20mg dapoxetine treatment, and 2.52 for the 40 mg dapoxetine treatment.The percentage of patients achieving increases of at least one minute inEL was higher in the 20 mg (22%) and 40 mg (24%) dapoxetine groups thanin the placebo group (14%).

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims. The above disclosure includesall the information believed to be essential to enable those skilled inthe art to practice the claimed invention.

The cited patents or publications may provide further useful informationand, thus, these cited materials are incorporated herein in theirentireties by reference thereto.

The results of a final analysis of a randomized, double-blind, three waycrossover evaluation of two prn doses of dapoxetine (20 mg and 40 mg) inthe treatment of premature ejaculation are disclosed in the followingtables. The final analyses of the data was conducted followingcompletion of all 3 treatment periods. TABLE 9 Ejaculatory Latency inMinutes for all Patients. Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LSMean) (LS Mean) (LS Mean) Ejaculatory Latency 2.26 2.78 3.19 (minutesp-value v. placebo for 0.0470 0.0004 ejaculatory latency Change inLatency 0.92 1.43 1.86 (minutes) p-value v. placebo for 0.05424 0.0004change in latency

TABLE 10a Ejaculatory Latency for Patients with a Baseline of Less ThanOne Minute. Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS Mean) (LSMean) (LS Mean) Ejaculatory Latency 1.1 1.2 1.7 (minutes) p-value v.placebo for 0.009 ejaculatory latency Change in Latency 0.5 0.6 1.3(minutes) p-value v. placebo for 0.008 change in latency

TABLE 10b Global Satisfaction for Patients with a Baseline of Less ThanOne Minute. Dapoxetin Dapoxetine Placebo 20 mg 40 mg p-value Better/MuchBetter  4% 13% 24% <0.001 ≧Slightly Better 16% 38% 46% <0.001

TABLE 11a Ejaculatory Latency for Patients with a Baseline of Less ThanTwo Minutes. Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS Mean) (LSMean) (LS Mean) Ejaculatory Latency 1.7 2.4 2.5 (minutes) p-value v.placebo for 0.003 ejaculatory latency Change in Latency 0.8 1.4 1.5(minutes) p-value v. placebo for 0.003 change in latency

TABLE 11b Global Satisfaction for Patients with a Baseline of Less ThanTwo Minutes. Dapoxetin Dapoxetine Placebo 20 mg 40 mg p-valueBetter/Much Better  7% 23% 29% <0.001 ≧Slightly Better 28% 50% 50%<0.001

Table 12 reveals that Dapoxetine can effectively and unexpectedly treatpremature ejaculation with the first dose administered to a patient.Thus, no lead-in period is required in order to treat prematureejaculation with dapoxetine providing for effective PRN dosing. TABLE 12Ejaculatory Latency Recorded After Administration of a Single Dose.Dapoxetine Dapoxetine Placebo 20 mg 40 mg (LS Mean) (LS Mean) (LS Mean)Ejaculatory Latency 1.54 ± 0.24 2.37 ± 0.24 1.98 ± 0.27 (minutes)p-value v. placebo for 0.015 0.219 ejaculatory latency*p-value for dapoxetine doses combined vs. placebo = 0.038

TABLE 13a Ejaculatory Latency for “Severe” Patients. DapoxetineDapoxetine Placebo 20 mg 40 mg Baseline (LS Mean) (LS Mean) (LS Mean)Ejaculatory Latency 1.23 2.10 2.60 3.09 (minutes) p-value, <0.0028Placebo vs 40 mg Change in Latency 0.92 1.42 1.93 (minutes) p-value,<0.0026 Placebo vs 40 mg

TABLE 13b Global Satisfaction for “Severe” Patients. DapoxetineDapoxetine Placebo 20 mg 40 mg p-value Better/Much Better  7.3% 17.2%25.5% <0.0001 ≧Slightly Better 31.0% 48.5% 54.1% <0.0001

TABLE 14a Ejaculatory Latency for “Moderate” Patients. DapoxetineDapoxetine Placebo 20 mg 40 mg Baseline (LS Mean) (LS Mean) (LS Mean)Ejaculatory Latency 1.68 2.10 2.64 2.93 (minutes) p-value, <0.0405Placebo vs 40 mg Change in Latency 0.45 0.94 1.27 (minutes) p-value,<0.0516 Placebo vs 40 mg

TABLE 14b Global Satisfaction for “Moderate” Patients. DapoxetineDapoxetine Placebo 20 mg 40 mg p-value Better/Much Better 13.4% 34.4%  50% <0.0076 ≧Slightly Better 30.1% 51.6% 66.7% <0.0076

TABLE 15a Ejaculatory Latency for Patients with a Baseline ≧Two Minutes.Placebo Dapoxetine 40 mg Baseline (LS Mean) (LS Mean) EjaculatoryLatency 3.19 5.24 6.59 (minutes) p-value, 0.18 Placebo vs 40 mg Changein Latency 2.12 3.43 (minutes) p-value, 0.19 Placebo vs 40 mg

TABLE 15b Global Satisfaction for Patients with a Baseline ≧ TwoMinutes. Dapoxetine Placebo 40 mg p-value Better/Much Better   13% 39.1%0.09 ≧Slightly Better 43.4% 65.2% 0.09

TABLE 16a Ejaculatory Latency for Patients with a Baseline ≧ One Minute.Dapoxetine Placebo 40 mg Baseline (LS Mean) (LS Mean) EjaculatoryLatency 1.90 3.16 4.24 (minutes) p-value, 0.01 Placebo vs 40 mg Changein Latency 1.32 2.40 (minutes) p-value, 0.01 Placebo vs 40 mg

TABLE 16b Global Satisfaction for Patients with a Baseline ≧ One Minute.Dapoxetine Placebo 40 mg p-value Better/Much Better 11.7% 36.4%<0.001 >Slightly Better 40.6% 65.0% <0.001

1. A method of treating or managing sexual dysfunction in a mammal inneed of treatment comprising administering on an as-needed basis to themammal an amount of a rapid-onset selective serotonin reuptake inhibitorthat is therapeutically effective in the absence of a priming dose. 2.The method of claim 1, wherein the mammal is a human male.
 3. The methodof claim 1, wherein the rapid-onset selective serotonin reuptakeinhibitor is short acting.
 4. The method of claim 1, wherein therapid-onset selective serotonin reuptake inhibitor is delivered in arapid release formulation.
 5. The method of claim 1, comprising theadditional step of administering a therapeutically effective amount of asecond therapeutic agent for treating or managing a sexual dysfunction.6. A method of treating or managing sexual dysfunction in a mammal inneed of such treatment comprising administering on an as-needed basis tothe mammal a therapeutically effective amount of dapoxetine or apharmaceutically acceptable salt thereof.
 7. The method of claim 6,wherein the mammal is a human male.
 8. The method of claim 6, comprisingthe additional step of administering a therapeutically effective amountof a second therapeutic agent for treating or managing sexualdysfunction.
 9. The method according to claim 6, wherein thetherapeutically effective amount of dapoxetine is from about 0.001 mg toabout 350 mg.
 10. The method of 6, wherein the therapeutically effectiveamount of dapoxetine or its pharmaceutically acceptable salt is fromabout 0.01 mg to about 200 mg.
 11. The method of 6, wherein thetherapeutically effective amount of dapoxetine or its pharmaceuticallyacceptable salt is from about 0.1 mg to about 120 mg.
 12. The method ofclaim 1 1, wherein dapoxetine or its pharmaceutically acceptable salt isadministered orally.
 13. The method of claim 12, wherein dapoxetine orits pharmaceutically acceptable salt is administered in an solid oraldosage form.
 14. The method of claim 13, wherein dapoxetine or itspharmaceutically acceptable salt is administered as a tablet or acapsule.
 15. The method of claim 6, wherein dapoxetine or itspharmaceutically acceptable salt is delivered as a rapid releaseformulation.